The overall goal of this program project is to investigate mechanisms by which alterations in mitochondrial protein function(s) contribute to neuronal degeneration related to Parkinson's disease (PD). Thus, a central Neuropathology Core to examine alterations in subcellular protein distribution, post-translational modification, and association with neuronal injury/death markers in PD/Lewy body disease (LBD) patient brain tissues and related model systems forms an essential component interfacing with each of the individual projects. The Core will be directed by a practicing neuropathologist with expertise in Lewy body diseases and subcellular protein trafficking in PD models, and draw upon extensive resources of the University of Pittsburgh Brain Bank. The neuropathology core will apply multi-label fluorescence or biochemical techniques to study protein localization, phosphorylation and macromolecular interactions in appropriately fixed or frozen tissues, in defining selection criteria to obtain pertinent regions of brain from diseased and matched control subjects, and in standardizing quantitative image analysis protocols for experimental material and human brain tissue studies across the projects. The core personnel have ongoing, productive collaborations with the individual project leaders, as reflected in shared manuscripts and preliminary data. Given the success of these interactions, we expect a continued expansion of translational efforts between disease models and human pathology.